Preparation of poly(acrylic acid)/tricalcium phosphate nanoparticles scaffold: Characterization and releasing UC-MSCs derived exosomes for bone differentiation.

Introduction: This study focused on preparing a multiscale three-dimensional (3D) scaffold using tricalcium phosphate nanoparticles (triCaPNPs) in a substrate of poly(acrylic acid) (PAA) polymer for controlled release of exosomes in bone tissue engineering. Methods: A scaffold was fabricated with a material mixture containing acrylic acid (AA) monomer, N,N'-methylenebisacrylamide (MBAA), ammonium persulfate (APS), sodium bicarbonate (SBC), and triCaPNPs called composite scaffold (PAA/triCaPNPs) via cross-linking and freeze-drying methods. The synthesis process was easy and without complex multi-steps. Through mimicking the hybrid (organic-inorganic) structure of the bone matrix, we here chose triCaPNPs for incorporation into the PAA polymer. After assessing the physicochemical properties of the scaffold, the interaction of the scaffold with human umbilical cord mesenchymal stem cells (UC-MSCs) such as attachment, proliferation, and differentiation to osteoblast cells was evaluated. In addition, we used DiI-labeled exosomes to verify the exosome entrapment and release from the scaffold. Results: The polymerization reaction of 3D scaffold was successful. Based on results of physicochemical properties, the presence of nanoparticles in the composite scaffold enhanced the mechanical stiffness, boosted the porosity with a larger pore size range, and offered better hydrophilicity, all of which would contribute to greater cell penetration, proliferation, and then better bone differentiation. In addition, our results indicated that our scaffold could take up and release exosomes, where the exosomes released from it could significantly enhance the osteogenic commitment of UC-MSCs. Conclusion: The current research is the first study fabricating a multiscale scaffold using triCaPNPs in the substrate of PPA polymer using a cross-linker and freeze-drying process. This scaffold could mimic the nanoscale structure and chemical combination of native bone minerals. In addition, our results suggest that the PAA/triCaPNPs scaffold could be beneficial to achieve controlled exosome release for exosome-based therapy in bone tissue engineering.

Disability accrual in primary and secondary progressive multiple sclerosis.

BACKGROUND: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. METHODS: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. RESULTS: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. CONCLUSIONS: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

Green Synthesized Iron-Coated Silver Nanoparticles: Economic Bimetallic Nanoparticles Potential Against Methicillin-Resistance Staphylococcus aureus.

Iron coating was introduced as one of the novel techniques to improve physicochemical and biological properties of silver nanoparticles (AgNPs). In the current experiment, impact of iron coating on the antimicrobial potency of AgNPs was investigated against methicillin-resistance Staphylococcus aureus (MRSA). To obtain more accurate data about the antimicrobial potency of examined nanostructures, the experiment was done on the 10 isolates of MRSA which were isolated from skin lesions. AgNPs and iron-coated AgNPs (Fe@AgNPs) were fabricated based on a green one-pot reaction procedure. Minimal inhibitory concentration (MIC) of Fe@AgNPs was not significantly different with MIC of AgNPs against eight out of 10 examined MRSA isolates. Also, by iron coating a reduction in the minimal inhibitory concentration (MIC) of AgNPs was observed against two MRSA isolates. The average MIC of AgNPs against 10 MRSA isolates was calculated to be 2.16 ± 0.382 mg/mL and this value was reduced to 1.70 ± 0.638 mg/mL for Fe@AgNPs. However, this difference was not considered significant statistically (P-value > 0.05). From productivity point of view, it was found that iron coating would improve the productivity of the synthesis reaction more than fivefold. Productivity of AgNPs was calculated to be 1.02 ± 0.07 g/L, meanwhile this value was 5.25 ± 0.05 g/L for Fe@AgNPs. Iron coating may provide another economic benefit to reduce final price of AgNPs. It is obvious that the price of a particular nanostructure made of silver and iron is significantly lower than that of pure silver. These findings can be considered for the fabrication of economic and potent antimicrobial nanoparticles.

External validation of a clinical prediction model in multiple sclerosis.

BACKGROUND: Timely initiation of disease modifying therapy is crucial for managing multiple sclerosis (MS). OBJECTIVE: We aimed to validate a previously published predictive model of individual treatment response using a non-overlapping cohort from the Middle East. METHODS: We interrogated the MSBase registry for patients who were not included in the initial model development. These patients had relapsing MS or clinically isolated syndrome, a recorded date of disease onset, disability and dates of disease modifying therapy, with sufficient follow-up pre- and post-baseline. Baseline was the visit at which a new disease modifying therapy was initiated, and which served as the start of the predicted period. The original models were used to translate clinical information into three principal components and to predict probability of relapses, disability worsening or improvement, conversion to secondary progressive MS and treatment discontinuation as well as changes in the area under disability-time curve (ΔAUC). Prediction accuracy was assessed using the criteria published previously. RESULTS: The models performed well for predicting the risk of disability worsening and improvement (accuracy: 81%-96%) and performed moderately well for predicting the risk of relapses (accuracy: 73%-91%). The predictions for ΔAUC and risk of treatment discontinuation were suboptimal (accuracy < 44%). Accuracy for predicting the risk of conversion to secondary progressive MS ranged from 50% to 98%. CONCLUSION: The previously published models are generalisable to patients with a broad range of baseline characteristics in different geographic regions.

Effects of Vitamin E on Neonatal Hyperbilirubinemia in Preterm Newborns.

Background: Neonatal jaundice indicates the presence of pigment in the skin and sclera. Vitamin E is an important component of the cellular antioxidant defense system. Here in the present study, we aimed to evaluate and investigate these therapeutic effects. Materials and Methods: This is a randomized clinical trial performed on 100 premature neonates. Group 1 received 10 units of Vitamin E daily for 5 days. The other group received placebo. Amount of bilirubin was measured at the time of 0, 24, 48, 72, and 96 h after birth. Results: Mean bilirubin in Vitamin E group was increasing until the 2nd day and then got a decreasing trend. In the control group, the increasing trend of bilirubin was going on till the 3rd day. Mean bilirubin increased significantly during the follow-up in both Vitamin E and control groups (χ2 [df] = 20.23 (1), P < 0.001). Although both groups showed an increasing trend in mean bilirubin, on the last day of follow-up, the average amount of increase was lower in Vitamin E group (5.06 ± 2.25 vs. 6.23 ± 3.98). Also in the 3rd and 4th days, mean bilirubin was lower in Vitamin E group. Conclusion: This study supports the usage of oral Vitamin E therapies on reducing the bilirubin levels in neonates. We also showed that this reduced trend occurs after day 3 of life, but in the follow-ups, neonates who were treated with Vitamin E had lower bilirubin levels compared to the placebo group.

Synthesis of mesoporous antimicrobial herbal nanomaterial-carrier for silver nanoparticles and antimicrobial sensing.

Herbal nanoparticles (HNPs) were introduced as a novel generation of antimicrobial nanoparticles. But in the battle against superbugs we need nanostructures with boosted antimicrobial potency. So in the current experiment, for the first time a green approach was developed for the silver functionalization of HNPs which were fabricated from an antimicrobial herb Thymus vulgaris. Silver functionalized HNPs (AgHNPs) were found to be mesoporous and were further fortified with antimicrobial compounds. The resulted structures were re-tested against MRSA and P. aeruginosa as superbugs. It was found that silver functionalization can provide eight-fold increase in the antimicrobial potency of HNPs. Moreover, MIC was reduced from 20 mg/mL to 2.5 mg/mL. Another eight-fold reduction in the MIC (0.3 mg/mL) was achieved by fortification with antimicrobial compounds. So, the antimicrobial potency of HNPs was successfully increase approximately up to 64-folds. Obtained results illustrated that silver functionalization and fortification with antimicrobial compounds can be considered as effective approaches to achieve HNPs with boosted antimicrobial potency. These nanostructures have the potency to be loaded with other antimicrobial compound such as antibiotics toward synergistic effects of AgNPs and antibiotics. Resulted nanostructures can be employed in the formulation of powerful topical and surface disinfectants against superbugs. Also, these particles can be considered as a next generation of boosted antimicrobial nanostructures.

The Efficacy of Integrating Spirituality into Prenatal Care on Pregnant Women's Sleep: A Randomized Controlled Trial.

OBJECTIVE: The study is aimed at determining the efficacy of spiritual content counselling on improving the sleep quality and insomnia severity of pregnant women. METHODS: This randomized controlled trial was carried out on 40 pregnant women recruited at five health centres of Abhar, Iran, 2020. The eligible women were allocated into two intervention and control groups according to the randomized blocking method. Group counselling with spiritual content was carried out in eight sessions at 16 to 20 weeks of gestation. The control group only received routine care. Data were collected using the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) questionnaires in three stages, before the intervention, at 28, and 36 weeks of gestation. Statistical analysis was performed using repeated measure ANOVA test, chi-square, and independent t-tests. P < 0.05 was considered significant statistical level. RESULTS: In the counselling group, the mean (SD) of a total score of sleep quality before the intervention was 9.45 (2.30) which decreased to 5.40 (1.56) in 36 weeks of gestational age, while in the control group was increased from 9.26 (2.15) to 11.47 (1.54). After the intervention based on the repeated measure ANOVA test, the mean total score of the insomnia severity, sleep quality, and its components decreased statistically in the second and third trimesters compared to the first trimester in the intervention group compared to the control group (P = 0.001). CONCLUSION: The results showed that counselling with spiritual content could effectively ameliorate sleep quality and reduce insomnia severity in pregnant women. It seems that the approach is an acceptable basis to design intervention programs in this field that can be considered by midwives. Clinical Trial Registry and Registration Number. The study was registered at the Iranian Registry of Clinical Trials under the IRCT20150731023423N15.

Utilization of Multiple Sclerosis Therapies in the Middle East Over a Decade: 2009-2018.

BACKGROUND: The multiple sclerosis (MS) landscape has changed over the past two decades across the world and in the Middle East. The Middle East is an ethnically diverse region located between 12° and 42° of latitude and 35° and 54° of longitude and varying altitudes. The magnitude of the shifts observed in the epidemiology and management of MS differ in each region and from country to country. OBJECTIVES: The aim of this study was to provide a clinicodemographic overview of the cohorts of patients contributed to MSBase, a large international MS registry, in the Middle East and describe disease-modifying treatment (DMT) utilization in the different countries within the region. Understanding the differences between these cohorts is integral to interpretation of the studies conducted using registry data and provides insight into clinical practice in these cohorts. METHODS: The MSBase registry was searched for patients with MS or clinically isolated syndrome from the Middle Eastern countries with data captured between 2009 and 2018. In 2-year epochs, and with special focus on the most recent epoch (2017-2018), we explored the demographic, clinical characteristics and treatment exposures of the studied cohorts and reported the results using standard descriptive statistics. RESULTS: Over the 10-year study period, 13,356 patients from 17 centers in 8 Middle Eastern countries fulfilled the inclusion criteria. The represented countries were Egypt, Iran, Kuwait, Lebanon, Oman, Saudi Arabia, Turkey and the United Arab Emirates. Overall, the represented cohort was young (median 36 years, quartiles 29-45) and captured relatively early after the onset of MS (median disease duration < 10 years, quartiles 3-12). The relapsing-remitting phenotype was the most prevalent phenotype in all countries (73-97%) and the highest proportion of progressive MS was reported in Saudi Arabia (12%). Median Expanded Disability Status Scale (EDSS) ranged from 0 to 3, depicting a mildly disabled cohort, with the exception of Saudi Arabia where the median EDSS was 4 (quartiles 1.5-6.5). The median relapse frequency was highest in Lebanon (median 1.03, 95% CI 0.94-1.16) followed by Egypt (median 1.02, 95% CI 0.89-1.24) and lowest in Saudi Arabia (median 0.70, 95% CI 0.58-0.95) and Kuwait (median 0.75, 95% CI 0.71-0.80). The treatment landscape greatly varied between different countries. Platform injectable therapies were mostly utilized in Egypt, Iran and Turkey (86%, 79% and 53%, respectively), while oral therapies and monoclonal antibodies were more commonly used in Kuwait, Lebanon and the United Arab Emirates (87.2%, 67.3% and 58.7%, respectively). CONCLUSION: Patients in the Middle East enrolled in a large multinational registry are representative of the general MS population. The spectrum of therapies used in the individual countries, however, is highly variable. Further studies that include rural and non-academic practices are needed to enhance our understanding of the MS cohorts in the Middle East.

Protocol for a multicentre, prospective cohort study of clinical, proteomic and genomic patterns associated with osteoporosis to develop a multidimensional fracture assessment tool: the PoCOsteo Study.

INTRODUCTION: The HORIZON 2020 project PoCOsteo aims (1) to develop a multidimensional fracture risk assessment tool which would take into account all factors known to be related to an individual's fracture risk. The fracture risk model is intended to be developed in two different populations, namely a European and a Middle Eastern one; (2) to develop a medical device, which would measure and/or quantify proteomic as well as genomic factors as present in whole blood samples collected through finger prick; (3) to test the clinical applicability and the validity of prototypes of the to be developed point of care device at both clinical centres. METHODS AND ANALYSIS: This article presents the protocol of this prospective cohort that will be carried out independently at two different centres (Division of Endocrinology and Diabetology at the Medical University of Graz (MUG) as a clinic-based cohort, and Endocrinology and Metabolism Research Institute (EMRI) at the Tehran University of Medical Sciences (TUMS) as a population-based cohort). The final aim is to develop a fracture risk assessment model, which would include clinical risk factors, biochemical markers of bone turnover, as well as specific genomic factors. The derivation cohorts will consist of individuals aged 50 years and above. The period of observation for each patient will be 12 months; an extension phase, which would last for another 2 years, is also planned. ETHICS AND DISSEMINATION: These studies are conducted in accordance with the World Medical Association Declaration of Helsinki. The Iranian part was approved by the Research Ethics Committee of EMRI, TUMS. The Austrian part was approved by the Ethics Committee of the Medical University of Graz. Based on the gathered information, a multidimensional fracture assessment tool will be designed which will later be added to the PoCOsteo device.

Development and Validation of Fear of Relapse Scale for Relapsing-Remitting Multiple Sclerosis: Understanding Stressors in Patients.

Chronic diseases are associated with patients' long-term stress and development of fear to things related to the source of stress. Better management of a patients' condition requires investigation of the underlying mechanisms that contribute to the process of development of chronic stress. Multiple Sclerosis (MS) is a debilitating chronic disease in most cases diagnosed after a relapse and characterized by the periodic occurrence of relapses in most patients. Due to the unpredictable course of the disease and relapses, patients with Relapsing-Remitting MS (RRMS) may deal with the stress of anticipation of relapse and its unpredictable consequences. The role of relapses and related stress on patients' quality of life has not been previously investigated. This study is the first effort to develop a self-report measure of Fear of Relapse (FoR) in patients with RRMS. Thirty-one items were extracted from in-depth clinical interviews with 33 RRMS patients to develop the preliminary version of the scale. Subsequently, 168 RRMS patients completed the questionnaire, the Intolerance of Uncertainty Scale (IUS) and Depression, Anxiety, and Stress Scale (DASS). Fifty-one patients completed the scale one more time a month later. Factor analysis revealed three components, and five items failed to load on any of them. To test the FoR's independence from similar measures, responses to 26 items were pooled once with DASS items and once with IUS items, and each time were subjected to confirmatory factor analysis (two-component solution). Despite significant correlations between FoR, DASS, and IUS Independent loadings of items belonging to FoR and DASS, and FoR and IUS revealed independence and unique contribution of FoR to the evaluation of patients. Cronbach's alpha for the 26-item version was 0.92. Test-retest reliability for total score was equal to 0.74. These findings provide preliminary evidence of the validity and reliability of the measure. This scale can help researchers and clinicians to have a more comprehensive understanding of patients' experience with the uncertain nature of MS, which is necessary for future efforts to address this stressor by targeting the underlying mechanism.

A Comparison Study of Efficacy and Safety of a Biosimilar Form of Intramuscular Βeta-interferon I-a Versus the Reference Product: A Randomized Controlled Clinical Trial in Iran.

We compared the efficacy and safety of a biosimilar form of beta-interferon-1a (Actovex) versus the reference product in the treatment of relapsing remitting multiple sclerosis (RRMS). In a double blind, randomized phase 3 clinical trial, we evaluated 138 patients with RRMS that were allocated to receive the biosimilar medication and the reference treatment (30 µg intramuscular, weekly for one year). We investigated changes in EDSS, relapse rate and MRI changes within one year. In sixty-nine patients who were allocated to each arm and analyzed mean age and its standard deviation was 32.4 ± 8.8 and 31.5 ± 8 for the biosimilar medication and the reference arm respectively. One-year follow-up revealed a mean difference of 0.084 in EDSS (95% CI: 0.069-0.237) between the two groups in favor of the biosimilar medication. This value did not exceed the predefined non-inferiority margin of 0.1. There were no statistically significant differences in relapse rate and systemic and local adverse events of the two groups. The results show that the biosimilar interferon 1-a is non-inferior to the reference product in terms of efficacy while it demonstrates comparable safety. In conclusion the biosimilar interferon 1-a can be considered as an effective and safe alternative to the reference product due to lower cost and more availability.

Inhibition of transforming growth factor-ß signaling pathway enhances the osteogenic differentiation of unrestricted somatic stem cells.

In recent years, extensive studies have been performed to enhance stem cell-based therapies for bone and cartilage repair. Among various sources of stem cells, cord blood-derived unrestricted somatic stem cells (USSCs) seem to be the most appropriate option for an autologous transplantation. Among different signaling pathways, the transforming growth factor-ß (TGF-ß) pathway is shown as an important regulator of proliferation and osteogenic differentiation in osteoblast progenitors as well as mesenchymal stem cells. Due to its contradictory and temporally variable effects on different cell types, we sought to investigate whether and how the TGF-ß signaling pathway regulates the osteogenic differentiation of the USSCs. Therefore, in the current study, we treated USSCs with the recombinant protein TGF-ß1 (1 ng/mL) and showed that the expression of matrix metalloproteinase 9, a well-known effector in this pathway, was significantly induced, indicating that the TGF-ß signaling pathway is active in USSCs. Then we applied a TGF-ß receptor antagonist (SB431542; 10 µM) to the osteogenic media cultured USSCs for single periods of 3.5 days within the 21-day differentiation period starting at day 0, 3.5, 7, 10.5, 14, and 17.5. The expression analysis results of the of the osteogenic marker runt-related transcription factor 2 as well as the production of bone matrix showed that SB431542 induced the osteogenic differentiation of USSCs more significantly during the early stage of differentiation, suggesting that the TGF-ß pathway temporally regulates the osteogenic differentiation of USSCs.

Investigating comparability of quantitative computed tomography with dual energy x-ray absorptiometry in assessing bone mineral density of patients with chronic spinal cord injury.

STUDY DESIGN: Psychometric study using retrospectively collected data. OBJECTIVES: We investigated the comparability of quantitative computed tomography (qCT) in assessing bone mineral density (BMD) with dual energy X-ray absorptiometry (DXA). We evaluated how well previously suggested normal values for spinal Hounsfield units (HU) correlated with routine DXA results in patients with chronic spinal cord injury (SCI). Furthermore, we investigated inter/intra-observer reliability of measuring HU in the spine. SETTING: Academic medical center in Tehran, Iran. METHODS: Spinal CT scans of 44 male participants with chronic SCI who had undergone DXA studies on the same day were selected. The main outcome measures were sensitivity, specificity, and area under curve (AUC) of HU at each spinal region against DXA results of areal BMD. The secondary outcome was inter/intra-observer reliability of measuring HU in the spinal column. RESULTS: We found no significant difference between qCT and DXA results (p-value = 0.237, R = 0.188). However, the two methods showed overall unfavorable comparability, with a sensitivity of 0%, 0%, and 80%, specificity of 50%, 90%, and 85%, and area under curve (AUC) of 0.27, 0.53, and 0.83 for cervical, thoracic, and lumbar spine, respectively. The best comparability was achieved at the lumbar region although not statistically significant (p-value = 0.072). Measuring HU was reliable (inter/intra-observer reliability >98%). CONCLUSIONS: This study demonstrates that currently proposed normal values result in unfavorable comparability in the cervical and thoracic regions; however, as the agreement improved at the lumbar spine, it is possible that qCT could become an indicator of bone strength with further research.

Evaluation of the effects of psychotherapy on anxiety among mothers of children with leukemia.

OBJECTIVE: Children with leukemia and their families face a long period of medical treatment and uncertainty about the future. These families may suffer from short- and long-term emotional problems. The aim of the present study was to assess the effect of supportive psychotherapy on the anxiety of mothers whose children suffer from leukemia. MATERIALS & METHODS: The current research were performed on mothers who had a child with leukemia hospitalized in Mofid Children's Hospital, Tehran, Iran. They were randomly selected. The research method was a quasi-experimental study with pretest/posttest design. The pretest Kettles' anxiety questionnaire was given to all the mothers and after seven sessions of supportive psychotherapy, the posttest was performed and the grades were compared. RESULTS: Ten mothers finished all seven therapeutic sessions. There was a statistically significant difference between the pretest and posttest mean scores, confirming the mothers' reduced anxiety level. CONCLUSION: Finding effective and newer approaches to improve the well-being of parents with a sick child is an important challenge of today's medical researches. Based on our findings, it is possible to reduce the anxiety in mothers of children with leukemia through supportive psychiatric therapies. KEYWORDS: Leukemia; Mothers; Anxiety; Psychology; Child.

In Vitro Activity of Tigecycline and Colistin against clinical isolates of Acinetobacter baumannii in Hospitals in Tehran and Bandar-Abbas, Iran.

BACKGROUND: The Acinetobacter species, particularly A. baumannii, has emerged as one of the main causes of nosocomial infections in recent years. The high prevalence of drug resistance in A. baumannii limits the therapeutic options for treating infections caused by these bacteria. The objective of this study was to determine the in vitro activity of Tigecycline and Colistin against clinical isolates of A. baumannii in Tehran and Bandar Abbas, Iran. METHODS: This study was conducted from March 2009 to November 2010 at three hospitals in Tehran and Bandar Abbas, Iran, using 165 Acinetobacter species isolated from clinical specimens. All isolates were subjected to PCR to detect bla OXA-51-like genes that are unique to Acinetobacter baumannii. Isolates that gave a band for the bla OXA-51-like genes were identified as A. baumannii. Anti-microbial susceptibility tests were performed for Tigecycline, Colistin, and other antibiotics. RESULTS: Sensitivity rates to Colistin and Polymyxin-B were 100%. Resistance rates for Tigecycline were 4.2% in Tehran and 8.8% in Bandar-Abbas according to Jones criteria, whereas, according to U.S. FDA criteria, the resistance rates were 20.8% and 17.6%, respectively. CONCLUSIONS: New alternative drugs are needed for the treatment of drug resistant A. baumannii. Although Colistin appears to be a good choice, adverse reactions have limited its usage. Tigecycline is effective against A. baumannii isolates, and it shows promise for solving the problem.